Tuesday, April 1, 2025
4/1/2025
Novel Therapeutic Strategies for Suppressing cGAS-STING Pathway in Alzheimer's Disease - Project Summary | Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuroinflammation and neuronal death. We recently identified a novel mechanism involving the upregulation of the AP-1 subunit c-Jun, leading to the decondensation of genomic regions containing retrotransposable elements (RTEs) and the formation and accumulation of RNA::DNA hybrids. Our study showed that accumulation of RNA::DNA hybrids activates the cGAS-STING pathway, leading to programmed cell death through the accumulation of cleaved caspase-3 (CC3) in various AD cell models, including cerebral organoids (COs). Targeting this RTEs-RNA::DNA hybrids-STING axis holds, therefore, promise as a therapeutic approach to counteract the neuroinflammatory response and cell death in AD. With this proposal, we aim to develop a novel therapeutic strategy for AD by targeting the activation of the RTEs-RNA::DNA hybrids-STING axis. In aim 1, we will generate intrabodies directed at neutralizing the RNA::DNA hybrids we reported to be present in CO models of sporadic AD (SAD) and familial AD (FAD). In aim 2, we will validate the intrabodies’ efficacy in suppressing cGAS-STING pathway activation in CO models of SAD and FAD. The intrabodies will be delivered via AAV vector, and the suppression of the cGAS-STING pathway will be assessed via immunofluorescence and western blot analysis. This therapeutic strategy could represent a potential breakthrough in treating AD, offering a precise and targeted approach to address one cause of abnormal cGAS-STING pathway activation. Importantly, the specificity of the intrabody-based strategy may reduce off-target effects, enhancing the safety and tolerability of therapeutic interventions. With this proposal, we seek to advance our understanding of AD pathogenesis and pave the way for the development of novel precision medicine treatments with the potential to reduce neuroinflammation and cell death, alleviating the neurodegeneration associated to this disease.
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